Novel oxazolidinone derivatives

ABSTRACT

The present invention relates to novel derivatives of oxazolidinone, a method thereof and pharmaceutical compositions comprising the derivatives for use in an antibiotic. The oxazolidinone derivatives of the present invention show inhibitory activity against a broad spectrum of bacteria and lower toxicity. The prodrugs, prepared by reacting the compound having hydroxyl group with amino acid or phosphate, have an excellent efficiency on solubility thereof against water. Further, the derivatives of the present invention may exert potent antibacterial activity versus various human and animal pathogens, including Gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, anaerobic microorganisms such as  Bacteroides  and  Clostridia , and acid-resistant microorganisms such as  Mycobacterium tuberculosis  and  Mycobacterium avium . Accordingly, the compositions comprising the oxazolidinone are used in an antibiotic.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.14/459,161 filed on Aug. 13, 2014, which is a Continuation of U.S.patent application Ser. No. 13/863,216 filed on Apr. 15, 2013, which isa Continuation of U.S. patent application Ser. No. 12/211,655 filed onSep. 16, 2008 (issued as U.S. Pat. No. 8,420,676), which is a Divisionalof U.S. patent application Ser. No. 10/596,412 filed on Jun. 13, 2006(issued as U.S. Pat. No. 7,816,379), which is a National Phaseapplication of PCT/KR04/03327, which claims priority toKR10-2003-0093342 and KR10-2004-0058809, the full disclosure of each ofwhich documents is hereby incorporated by reference in its entiretyherein.

BACKGROUND OF THE INVENTION

Technical Field

The present invention relates to novel derivatives of oxazolidinone,preparation methods of the same, and pharmaceutical compositionscomprising the same for use in an antibiotic.

Description of the Related Art

Used as orally administrable antibacterial agents, oxazolidinonecompounds are not products of fermentation, but artificially synthesizedones, and various structures of their derivatives are known. Forinstance, 3-phenyl-2-oxazolidinone derivatives having one or twosubstituents are stated in U.S. Pat. Nos. 4,948,801, 4,461,773,4,340,606, 4,476,136, 4,250,318 and 4,128,654. 3-[(Monosubstituted)phenyl]-2-oxazolidinone derivatives of Formula 2 are disclosed in EP0312000, J. Med. Chem. 32, 1673 (1989), J. Med. Chem. 33, 2569 (1990),Tetrahedron, 45, 123 (1989), etc.

Pharmacia & Upjohn developed oxazolidinone derivatives of Formulas 3 and4 (WO 93/23384, WO 95/14684 and WO 95/07271). Having succeeded ingaining the approval of the Food and Drug Administration (FDA) ofU.S.A., the oxazolidinone derivative of Formula 3, by the name of‘Zyvox’, has come into the market. However, these conventional syntheticoxazolidinone compounds were found to suffer from the disadvantage ofshowing antibacterial activity against a narrow spectrum of bacteria,being toxic to humans, and being poor in therapeutic activity in vivo.Zyvox may be used restrictively as injection since the solubility ofZyvox against water is inadequate for use in injection, which is about 3mg/ml.

Further, WO 93/09103 discloses derivatives of phenyl oxazolidinone,substituted with heterocyclics such as thiazole, indole, oxazole andquinole, as well as pyridine, at position 4 of the phenyl ring. However,these derivatives of oxazolidinone are known as providing insufficientmedicinal effects because the heterocyclics bear simple substituentssuch as alkyl or amino groups.

In WO 01/94342, synthesizing derivatives of phenyl oxazolidinone, havingwith pyridine or derivatives of phenyl at position 4 of the phenyl ringwas described. The compounds synthesized are potent in inhibitoryactivity against a broad spectrum of bacteria and are also superiorantibiotic to Zyvox. However, The compounds are unable to be formulatedas injection because solubility of the same is under 30 μg/ml.

Accordingly, the intensive and thorough research on oxazolidinonederivatives, conducted by the present inventors aiming to overcome theabove problems encountered in prior arts, resulted in the findingoxazolidinone derivatives as well as prodrugs thereof, wherein theprodrugs are prepared by reacting amino acid or phosphate with theoxazolidinone derivatives having hydroxyl group. Further, salts of theoxazolidinone derivatives prodruged were easily synthesized by usingamine group of amino acid of the same to synthesize organic acid orinorganic acid and by using a hydroxyl group of phosphate and oneselected from sodium and calcium. The oxazolidinone derivatives haveexcellent effects on antibiotic activity and the solubility of the sameis greatly enhanced.

SUMMARY OF THE INVENTION Disclosure of the Invention Technical Problem

It is an object of the present invention to provide novel derivatives ofoxazolidinone.

It is another object of the present invention to provide a method ofpreparing the above-mentioned derivatives.

It is still another object of the present invention to provide apharmaceutical composition comprising the above-mentioned derivativesfor use in an antibiotic.

Technical Solution

The present invention provides novel derivatives of oxazolidinonecorresponding to Formula 1 defined below.

In the Formula 1, X represents carbon or nitrogen.

R₁ and R₁′ respectively represent hydrogen or fluorine.

R₂ represents —NR₅R₆, —OR₇, triazol, fluorine, alkylphosphate,monophosphate or a metal salt of phosphate;

R₅ and R₆, which are the same or different, respectively representhydrogen, C. sub. 1-4 alkyl group or acetyl; and

R₇ is hydrogen, C. sub. 1-3 alkyl group or acylated amino acid. When theR₇ is acylated amino acid, amino acid refers to alanine, glycine,proline, isoleucine, leucine, phenylalanine, β-alanine or valine.

Het, which is a heterocyclic ring or a hetero aromatic ring, refers topyrrole, furan, piperazine, piperidine, imidazole, 1,2,4-triazol,1,2,3-triazol, tetrazole, pyrazole, pyrrolidine, oxazole, isoxazole,oxadiazole, pyridin, pyrimidine, thiazole or pyrazine.

R₃ and R₄, which are the same or different, respectively refer tohydrogen, C. sub. 1-4 alkyl group that is substituted or unsubstitutedwith cyano, —(CH₂)m-OR₇ (m represents 0, 1, 2, 3, 4) or ketone.

The derivatives of oxazolidinone corresponding to Formula 1 may be usedfor a pharmaceutically acceptable salt, it is preferably an acidaddition salt prepared by using pharmaceutically acceptable free acid.The free acid may be inorganic or organic. The inorganic free acid maycomprise hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid,etc. The organic free acid may include citric acid, acetic acid, lacticacid, maleic acid, fumaric acid, gluconic acid, methane sulfonic acid,glyconic acid, succinic acid, 4-toluenesulfonic acid, trifluoroaceticacid, galuturonic acid, embonic acid, glutamic acid, aspartic acid, etc.

Preferred compounds of the oxazolidinone derivatives according to thepresent invention include the following compounds and their structuresare described in Table 1.

-   1)    (S)-3-(4-(2-(2-oxo-4-glycyloxymethylpylolidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide trifluoroacetic acid,-   2)    (S)-3-(4-(2-(4-glycyloxymethyl-1,2,3-triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide trifluoroacetic acid,-   3)    (S)-3-(4-(2-(5-glycyloxymethylisoxazol-3-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide trifluoroacetic acid,-   4)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,4]triazol-1-yl)methyl    oxazolidin-2-on,-   5)    (S)-3-(4-(2-(2-oxo-3-glycyloxypyrolidine-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide trifluoroacetic acid,-   6)    (S)-3-(4-(2-(5-glycyloxymethyl-[1,2,4]oxadiazole-3-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide trifluoroacetic acid,-   7)    (S)-3-(4-(2-(5-glycyloxymethyl-4,5-dihydroisoxazole-3-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide trifluoroacetic acid,-   8)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-2-yl)methyl    oxazolidin-2-on,-   9)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyl    oxazolidin-2-on,-   10)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl    oxazolidin-2-on,-   11)    (S)-3-(4-(4-(4,5-dimethyloxazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide,-   12)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl    oxazolidin-2-on trifluoroacetic acid,-   13)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyl    oxazolidin-2-on,-   14)    (R)-3-(4-(2-([1,2,4]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyl    oxazolidin-2-on,-   15)    (S)-3-(4-(2-(4,5-dimethyloxazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl    acetamide,-   16)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl    oxazolidin-2-on,-   17) (R)-3-(4-(2-[1,2,4]triazol-1-yl    pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on,-   18)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoromethyl    oxazolidin-2-on,-   19)    (S)-3-(4-(2-(imidazole-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-aminomethyl    oxazolidin-2-on hydrochloride,-   20)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyl    oxazolidin-2-on trifluoroacetic acid,-   21)    (R)-3-(4-(4-(4,5-dimethyloxazol-2-yl)phenyl)-3-fluorophenyl)-5-hydroxymethyl    oxazolidin-2-on,-   22)    (R)-3-(4-(2-([1,2,3]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl    oxazolidin-2-on trifluoroacetic acid,-   23)    (R)-3-(4-(4-(4,5-dimethyloxazol-2-yl)phenyl)-3-fluorophenyl)-5-glycyloxymethyl    oxazolidin-2-on trifluoroacetic acid,-   24)    (R)-3-(4-(2-([1,2,3]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl    oxazolidin-2-on,-   25)    (S)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide,-   26)    (S)-3-(4-(4-(4(S)-hydroxymethyl-4,5-dihydroxazole-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide,-   27)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazole-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl    oxazolidin-2-on trifluoroacetic acid,-   28)    (S)-3-(4-(4-(4-hydroxymethylthiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide,-   29)    (R)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl    oxazolidin-2-on,-   30)    (S)-3-(4-(4-(4-glycyloxymethylthiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide trifluoroacetic acid,-   31) (S)-3-(4-(4-(4-cyanomethyl    thiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl    acetamide,-   32) (R)-3-(4-(4-(4-cyanomethyl    thiazol-2-yl)phenyl)-3-fluorophenyl)-5-hydroxymethyl    oxazolidin-2-on,-   33)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methoxymethyl    oxazolidin-2-on,-   34) (R)-3-(4-(4-(4-cyanomethyl    thiazol-2-yl)phenyl)-3-fluorophenyl)-5-glycyloxymethyl    oxazolidin-2-on trifluoroacetic acid,-   35)    (R)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl    oxazolidin-2-on trifluoroacetic acid,-   36) (R)-3-(4-(4-(4-hydroxymethyl    thiazol-2-yl)phenyl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyl    oxazolidin-2-on,-   37) (R)-3-(4-(4-(4-glycyloxymethyl    thiazol-2-yl)phenyl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyl    oxazolidin-2-on trifluoroacetic acid,-   38)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3,5-difluorophenyl)-5-hydroxymethyl    oxazolidin-2-on,-   39)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3,5-difluorophenyl)-5-hydroxymethyl    oxazolidin-2-on,-   40)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(N,N-dimethylaminomethyl)oxazolidin-2-on,-   41)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(N-methylaminomethyl)oxazolidin-2-on,-   42)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyl    oxazolidin-2-on trifluoroacetic acid,-   43)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyl    oxazolidin-2-on hydrochloride,-   44)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyl    oxazolidin-2-on hydrochloride,-   45)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl    oxazolidin-2-on hydrochloride,-   46)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-prolinyloxy)methyl    oxazolidin-2-on trifluoroacetic acid,-   47)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-prolinyloxy)methyl    oxazolidin-2-on hydrochloride,-   48)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl    oxazolidin-2-on hydrochloride,-   49)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyl    oxazolidin-2-on trifluoroacetic acid,-   50)    (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyl    oxazolidin-2-on hydrochloride,-   51)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyl    oxazolidin-2-on trifluoroacetic acid,-   52)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyl    oxazolidin-2-on hydrochloride,-   53)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyl    oxazolidin-2-on trifluoroacetic acid,-   54)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyl    oxazolidin-2-on hydrochloride,-   55)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-prolinyloxy)methyl    oxazolidin-2-on trifluoroacetic acid,-   56)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-prolinyloxy)methyl    oxazolidin-2-on hydrochloride,-   57)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyl    oxazolidin-2-on trifluoroacetic acid,-   58)    (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyl    oxazolidin-2-on hydrochloride,-   59)    (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl    disodiumphosphate,-   60)    (R)-[3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl    disodiumphosphate,-   61)    (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl    oxazolidin-2-on,-   62)    (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl    oxazolidin-2-on trifluoroacetic acid,-   63)    (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl    oxazolidin-2-on hydrochloride,-   64)    (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)    methyl oxazolidin-2-on trifluoroacetic acid,-   65)    (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)    methyl oxazolidin-2-on hydrochloride,-   66)    (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)    methyl oxazolidin-2-on trifluoroacetic acid,-   67)    (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)    methyl oxazolidin-2-on hydrochloride,-   68)    (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyl    oxazolidin-2-on trifluoroacetic acid,-   69)    (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)    methyl oxazolidin-2-on hydrochloride,-   70)    (R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl    disodiumphosphate,-   71)    (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyl    oxazolidin-2-on,-   72)    mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate,    and-   73)    mono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate.

TABLE 1 Compound Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

In Table 1, ‘Ac’ represents acetyl and ‘TfOH’ refers to trifluoroaceticacid.

Further, the present invention provides a method of preparing thederivatives of oxazolidinone corresponding to Formula 1, as shown inScheme 1 is defined below.

In the Scheme 1, Z represents C₁₋₄ alkyl group, X, R₁, R₁′, R₂, R₃ andR₄ are as defined in Formula 1 and Y represents halogen.

The method of preparing the derivatives of oxazolidinone according tothe present invention comprises:

-   -   substituting a halogen atom for a hydrogen atom on phenyl of a        derivative (II) of hydroxymethyloxazolidinone thereby to form a        derivative (III)(Step 1);    -   substituting stannyl for a halogen atom (Y) of the        derivative (III) to form a derivative (IV)(Step 2);    -   reacting the derivative (IV) with pyridine or phenyl derivative        that is substituted to bromine or iodine to form a        derivative (V) of oxazolidinone having pyridine ring or phenyl        ring (Step 3); and    -   reacting the derivative (V) with amino acid having a protecting        group and then with acid thereby to eliminate the protecting        group and to form salts of the compounds corresponding to        Formula 1, or subjecting the derivative (V) to react with        phosphate and then with metallic salt thereby to form salts of        the compounds corresponding to Formula 1 (Step 4).

In the Step 1, the derivative (II) of hydroxymethyloxazolidinone may besynthesized by conventional methods. For example, a method may comprisesubstituting an amino group of anilin for a benzyloxycarbonyl group andreacting a substituted compound with glycidylbutylate in a state ofstrong bases thereby to form the derivative (II). The state may beprepared by adding a strong base; preferably the strong base may includen-butyllitium, sec-butyllitium, tert-butyllitium, etc., more preferablyn-butyllitium. Further, it is preferable to subject the method at atemperature of about 78° C. in liquid nitrogen.

The Step 1 is subjected to substitute a hydrogen atom of phenyl group ofthe derivative (II) for a halogen atom, preferably for an iodine atom.When the hydrogen atom is substituted for the iodine atom, thesubstituted reaction may be subjected preferably by adding iodinemonochloride (ICI) or trifluoroacetic acid silver salt (CF₃COOAg) andadding iodine at room temperature.

The Step 2 is subjected the derivative (III) to react withhexamethylditin, hexabutylditin or tributyltin hydride by adding acatalyst of palladium to form the derivative (IV) of which iodine atomis substituted for a trimethylstannyl group or a tributylstannyl group.The catalyst of palladium may comprise dichlorobistriphenylphosphinepalladium (II), tetrakistriphenylphosphine palladium (0), etc. It ispreferred to carry out the Step 2 in a solvent of 1,4-dioxan,dimethylformamide, tetrahydrofuran, 1-methyl-2-pyrolidone, etc. at atemperature of about 90 to 150° C.

The Step 3 is carried out by reacting the derivative (IV) with acompound having hetero ring on phenyl or pyridine ring thereby to formthe derivative (V). A catalyst of palladium added in the Step 3 may beidentical to that of palladium in Step 2. It is preferred to carry outthe Step 3 in a solvent of dimethylformamide, 1-methyl-2-pyrolidone,etc. at a temperature of about 100 to 120° C.

The Step 4 is performed by reacting the derivative (V) with amino acidthat is protecting an amino group with t-butyloxycarbonyl,dicyclohexylcarbodiimide and 4-dimethylaminopyridine thereby to form thederivative (I) having amino group. The amino acid may include alanine,glycine, proline, isoleucine, leucine, phenylalanine, 0-alanine, valine,etc. A solvent comprises dimethylformamide, 1-methyl-2-pyrolidone, etc.Preferably, a reaction by adding the derivative (V) with amino acid iscarried out by stirring for about 5 hours above at room temperature.

A mixture of the derivative (V) and amino acid reacts to a strong acidsuch as trifluoroacetic acid, etc. to eliminate a protecting group. Thesolvent is removed from the mixture and the mixture is crystallizedthereby to provide a salt of the derivative of oxazolidinonecorresponding to Formula 1. Preferably, a reaction by adding thederivative (V) with amino acid is carried out by stirring for about 2hours above at room temperature.

The salt of the derivative of formula 1, prepared by using amino acid atposition R₃ or R₄, in a method known similarly to the above method, maybe gained.(S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide as a starting material in the method is known and the methodis described in WO0194342.

Further, a phosphate metallic salt of the derivative (I) may be formedby adding sodiummethoxide, sodium hydroxide, etc. to a composition in asolvent such as methanol, ethanol etc., the composition is prepared bydissolving the derivative (V) in trimethylphosphate ortriethylphosphate, adding phosphorous oxy chloride and stirring forabout 12 hours at room temperature. The phosphate metallic salt may beproduced by reacting the derivative (V) with tetrazole and derivates ofamidite at room temperature, oxidizing a reacted compound, synthesizinga derivative of alkylphosphate, eliminating alkyl group using a strongacid thereby to form a derivative of phosphate acid, and converting thederivative of phosphate acid into the phosphate metallic salt by theabove-mentioned method.

Further, the present invention provides a pharmaceutical compositioncomprising the derivatives of oxazolidinone corresponding to Formula 1for use in an antibiotic.

The oxazolidinone derivatives of the present invention show inhibitoryactivity against a broad spectrum of bacteria, against methicillinresistant Staphylococcus aureus (MRSA) and vancomycin resistantEnterococci (VRE) and have excellent relatively antibiotic activity witha relatively low concentration thereof or in vivo.

Further, the derivatives of the present invention may exert potentantibacterial activity versus various human and animal pathogens,including Gram-positive bacteria such as Staphylococi, Enterococci andStreptococi, anaerobic microorganisms such as Bacteroides andClostridia, and acid-resistant microorganisms such as Mycobacteriumtuberculosis and Mycobacterium avium.

The derivatives of oxazolidinone, having hydroxyl, are reacted withamino acid or phosphate to form prodrugs thereof. The prodrugs havesuperior solubility to compounds that are not formed as prodrugs: thesolubility of the prodrugs represents above 28 mg/ml and the solubilityof the compound 10 mg/ml (compound 10). The prodrugs stabilize in wateror acidic solution and change to hydroxylmethyl compounds by beingreverted using esterase and phosphatase in a blood thereby to developeasy formulation for injection or oral administration.

The composition of the present invention may comprise at least oneeffective ingredient having functions similar to those of thederivatives of oxazolidinone.

For formulating a pharmaceutical composition, at least one specie of thecompound of formula 1 may be admixed with at least one pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may includesaline solution, sterile water, Ringer's solution, buffered salinesolution, dextrose solution, malto-dextrin solution, glycerol, ethanol,etc. According to the user's necessity, the pharmaceutical compositionmay contain conventional expedient such as antioxidizing agent, buffer,soil cleaner, etc. Also, the compositions are admixed with diluents,disintegrants, surface active agents, binders, lubricants, aqueoussolution, suspension, etc. to be formed for injection, powders,capsules, granules, tablet, etc. Preferably, the formulation is preparedusing proper methods described in Remington's Pharmaceutical Science(the newest edition), Mack Publishing Company, Easton Pa., etc.according to diseases or ingredients.

The compound of the present invention may be administrated orally orparenterally, such as intravenously, hypodermically, intra-abdominally,topically, etc. The dosage of the compound may vary depending upon theparticular compound utilized, the mode of administration, the condition,and severity thereof, of the condition being treated, as well as thevarious physical factors related to the individual being treated. Asused in accordance with invention, satisfactory results may be obtainedwhen the compounds of the present invention are administered to theindividual in need at a daily dosage of about 10 mg to about 25 mg perkilogram of body weight, preferably about 13 mg to about 20 mg perkilogram of body weight, more preferably administered each of divideddoses to many times per day.

The Lethal Dose (LD₅₀) of the oxazolidinone derivatives shows above 1g/kg in test of acute toxicity so that the derivatives are found stable.

(a) Advantageous Effects

The oxazolidinone derivatives of the present invention show inhibitoryactivity against a broad spectrum of bacteria and lower toxicity. Theprodrugs, prepared by reacting the compound having hydroxyl with aminoacid or phosphate, have high solubility thereof against water.

Further, the derivatives of the present invention may exert potentantibacterial activity versus various human and animal pathogens,including Gram-positive bacteria such as Staphylococi, Enterococci andStreptococi, anaerobic microorganisms such as Bacteroides andClostridia, and acid-resistant microorganisms such as Mycobacteriumtuberculosis and Mycobacterium avium.

Accordingly, the compositions comprising the derivatives ofoxazolidinone are used in an antibiotic.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT (b) Best Mode forCarrying Out the Invention

The examples are given solely for the purpose of illustration and arenot to be construed as limitations of the present invention, as manyvariations thereof are possible without departing from the spirit andscope of the invention.

Preparation Example 1 Preparation of N-Carbobenzyloxy-3-fluoroaniline

3-fluoroaniline 100 g was dissolved in 1 L of tetrahydrofuran (THE) andthe solution was added with 150 g (1.8 mol) of sodium bicarbonate(NaHCO₃). After being cooled to 0° C., the solution was slowly addedwith 154 ml of N-carbobenzyloxy chloride (CbzCl) for reaction. While thetemperature was maintained at 0° C., the reaction mixture was let toreact for 2 hours with stirring. Afterwards, the reaction was extractedwith 0.5 L of ethyl acetate. The organic layer, after being separated,was washed with brine, dried over anhydrous magnesium sulfate (MgSO₄)and concentrated in vacuo. The residue was washed twice with n-hexane toafford the title compound as white crystal. 132 g. Yield 85%.

Preparation Example 2 Preparation of(R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

132 g of N-carbobenzyloxy-3-fluoroaniline 132 g prepared in thePreparation example 1 was dissolved in 1.3 L of tetrahydrofuran and thesolution was cooled to −78° C. 370 ml of n-buthyllitium (n-BuLi,1.6M/n-hexane) was slowly added to the solution in a nitrogenatmosphere, followed by stirring for 10 min. And 84 ml of(R)-(−)-glycidylbuthylate was slowly added to the reaction mixture,stirred at the same temperature for 2 hours and allowed to react for 24hours at room temperature. After completion of the reaction, thesolution was added with ammonium chloride (NH₄Cl) solution and extractedwith 0.5 L of ethyl acetate at room temperature. The organic layer, thusseparated, was washed with brine, dried over anhydrous magnesium sulfateand concentrated in vacuo. The residue was dissolved in 100 ml of ethylacetate and washed with n-hexane to give white crystals, which werepurified to the title compound. 80 g. Yield 70%.

¹H NMR (DMSO-d₆) δ 7.85 (t, 1H), 7.58 (dd, 1H), 7.23 (dd, 1H), 4.69 (m,1H), 4.02 (t, 1H), 3.80 (dd, 1H), 3.60 (br dd, 2H).

Preparation Example 3 Preparation of(R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

In 300 ml of acetonitryl was dissolved 30 g of(R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in thePreparation example 2, and 46 g of trifluoroacetic acid silver salt(CF₃COOAg) and 43 g of iodide were added to the solution. After beingstirred for one day at room temperature, the solution was added withwater and was extracted with ethyl acetate. The organic layer, thusseparated, was washed with brine and dehydrated. And then the residuewas filtered, concentrated in vacuo and dried thereby to form the titlecompound 44g. Yield 94%.

¹H NMR (DMSO-d₆) δ 7.77 (t, 1H), 7.56 (dd, 1H), 7.20 (dd, 1H), 5.20 (m,1H), 4.70 (m, 1H), 4.07 (t, 1H), 3.80 (m, 1H), 3.67 (m, 2H), 3.56 (m,3H)

Preparation Example 4 Preparation of(R)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

In 660 ml of 1,4-dioxan was dissolved 50 g of(R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared inthe Preparation example 3, 52 g of hexabutylditin ((Bu₃Sn)₂) and 9.3 gof dichlorobistriphenylphosphinpalladium were added into the solution,and stirred for 2 hours. The solution was filtered using celite andconcentrated in vacuo. The residue was purified by column chromatographyand 45 g of the title compound was formed.

¹H NMR (DMSO-d₆) δ 7.74 (m, 3H), 5.20 (t, 1H), 4.71 (m, 1H), 4.08 (t,1H), 3.82 (dd, 1H), 3.68 (m, 1H), 3.52 (m, 1H), 1.48 (m, 6H), 1.24 (m,6H), 1.06 (m, 6H), 0.83 (t, 9H)

Preparation Example 5 Preparation of 2-cyano-5-bromopyridine

In 1 L of dimethylformamide was dissolved 100 g of 2,5-dibromopyridine,32 g of cupper cyanide and 17.8 g of sodium cyanide were added to thesolution at room temperature and the solution was stirred at thetemperature of 150° C. for 7 hours for reaction. After being cooled toroom temperature, the reaction mixture was added with water andextracted with ethyl acetate. The organic layer was washed with brine,dehydrated, filtered and concentrated in vacuo. The title compound 54gwas obtained. Yield 70%.

¹H NMR (CDCl₃) δ 8.76 (s, 1H), 7.98 (dd, 1H), 7.58 (dd, 1H)

Preparation Example 6 Preparation of 2-(tetrazol-5-yl)-5-bromopyridine

10 g of 2-cyano-5-bromopyridine prepared in the Preparation example 5was dissolved in 100 ml of dimethylformamide, 5.33 g of sodiumazide, and4.4 g of ammoniumchloride were added to the solution at roomtemperature, and the solution was stirred at the temperature of 110° C.for 3 hours for reaction. The reaction mixture was added with water andthen was extracted with ethyl acetate. The organic layer, thusseparated, was washed with brine, dehydrated, filtrated and concentratedin vacuo thereby to obtain 10.5 g of the title compound. Yield 85%.

Preparation Example 7 Preparation of2-(1-methyltetrazol-5-yl)-5-bromopyridine and2-(2-methyltetrazol-5-yl)-5-bromopyridine

10.5 g of 2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparationexample 6 was dissolved in 100 ml of dimethylformamide. And then 6.5 gof sodiumhydroxide was added to the solution and 9.3 g of iodomethanewas slowly added to the solution at the temperature of 0° C. Thesolution was stirred for 6 hours at room temperature, added with water,extracted with ethyl acetate. And then the organic layer was washed withbrine, dehydrated, filtrated, concentrated in vacuo and purified bycolumn chromatography to obtain 4 g of2-(1-methyltetrazol-5-yl)-5-bromopyridine and 5 g of2-(2-methyltetrazol-5-yl)-5-bromopyridine.

1) 2-(1-methyltetrazol-5-yl)-5-bromopyridine

¹H NMR (CDCl₃) δ 8.77 (t, 1H), 8.23 (dd, 1H), 8.04 (dd, 1H), 4.46 (s,3H)

2) 2-(2-methyltetrazol-5-yl)-5-bromopyridine

¹H NMR (CDCl₃) δ 8.80 (t, 1H), 8.13 (dd, 1H), 7.98 (dd, 1H), 4.42 (s,3H)

Preparation Example 8 Preparation of2-(2-methyl-[1,3,4]oxadiazol-5-yl)-5-bromopyridine

In 130 ml of acetic anhydride was dissolved 8.6 g of2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparation example 6.And then the solution was added with 15 ml of pyridine and stirred for 3hours for reaction. The reaction mixture was added with ethyl acetateand extracted to separate organic layer. And then the organic layer waswashed with water and brine. The organic layer was dehydrated, filtratedand concentrated in vacuo to give 7.3 g of the title compound. Yield80%.

¹H NMR (CDCl₃) δ 7.99 (t, 1H), 7.40 (dd, 1H), 7.27 (dd, 1H), 1.83 (s,3H)

Preparation Example 9 Preparation of2-([1,2,3]triazol-1-yl)-5-bromopyridine and2-([1,2,3]triazol-2-yl)-5-bromopyridine

20 g of 2,5-dibromopyridine was dissolved in 200 ml of1-methyl-2-pyrrolidone. The solution was added with 35 g ofpotasiumcarbonate and stirred for 10 hours at the temperature of 100° C.The reaction mixture was added with ethyl acetate and the organic layer,thus obtained was washed with water and brine. The organic layer wasdried, filtered and concentrated in vacuo to provide 6 g of2-([1,2,3]triazol-1-yl)-5-bromopyridine, 4 g of2-([1,2,3]triazol-2-yl)-5-bromopyridine.

1) 2-([1,2,3]triazol-1-yl)-5-bromopyridine

¹H NMR (CDCl₃) δ 8.53 (dd, 2H), 8.10 (d, 1H), 8.03 (dd, 1H), 7.82 (s,1H)

2) 2-([1,2,3]triazol-2-yl)-5-bromopyridine

¹H NMR (CDCl₃) δ 8.60 (t, 1H), 7.97 (s, 2H), 7.87 (s, 2H)

Example 1 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-on (compound 10)

In 150 ml of 1-methyl-2-pyrrolidone was dissolved 37 g of(R)-3-(4-tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol.The solution was added with 19.7 g of2-(2-methyltetrazol-5-yl)-5-bromopyridine, 10.44 g of lithium chlorideand 2.9 g of dichlorobistriphenylphospine palladium (II) at roomtemperature and then stirred at the temperature of 120° C. for 4 hours.The reaction mixture was added with water and then extracted with ethylacetate. The organic layer, thus separated, was washed with brine,dehydrated, filtrated, concentrated in vacuo and purified by columnchromatography to provide 8 g of the title compound. Yield 26%.

¹H NMR (DMSO-d₆) δ 8.90 (s, 1H), 8.18 (m, 2H), 7.70 (m, 2H), 7.49 (dd,1H), 5.25 (t, 1H), 4.74 (m, 1H), 4.46 (s, 3H), 4.14 (t, 1H), 3.88 (dd,1H), 3.68 (m, 1H), 3.58 (m, 1H)

Example 2 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-on (compound 16)

The title compound 6.6 g (yield 30%) was prepared in a method similar tothat of Example 1, except that, 14.3 g of2-(2-methyl-[1,3,4]oxadiazol-5-yl)-5-bromopyridine, instead of2-(2-methyltetrazol-5-yl)-5-bromopyridine, was used as a startingmaterial.

¹H NMR (DMSO-d₆) δ 8.93 (s, 1H), 8.21 (s, 2H), 7.71 (m, 2H), 7.50 (dd,1H), 5.25 (t, 1H), 4.74 (m, 1H), 4.14 (t, 1H), 3.89 (dd, 1H), 3.68 (m,1H), 3.59 (m, 1H), 2.64 (s, 3H)

Example 3 Preparation of(R)-3-(4-(2-([1,2,4]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-on (compound 17)

The same procedure as in Example 1 was conducted, except for using,instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 200 mg of2-([1,2,4]triazol-1-yl)-5-bromopyridine as a starting material, toprepare the title compound 150 mg (yield 48%).

Example 4 Preparation of(R)-3-(4-(4-(4,5-dimethyloxzol-2-yl)phenyl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-on (compound 21)

The same procedure as in Example 1 was conducted, except for using,instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 1 g of4-(4,5-dimethyloxazol-2-yl)bromobenzene as a starting material, toprepare the title compound 780 mg (yield 76%).

¹H NMR (DMSO-d₆) δ 7.96 (s, 1H), 7.94 (s, 1H), 7.63 (m, 4H), 7.44 (dd,1H), 5.23 (t, 1H), 4.72 (m, 1H), 4.12 (t, 1H), 3.87 (dd, 1H), 3.68 (m,1H), 3.56 (m, 1H), 2.32 (s, 3H), 2.10 (s, 3H)

Example 5 Preparation of(R)-3-(4-(2-([1,2,3]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-on(compound 24)

The same procedure as in Example 1 was conducted, except for using,instead of 2 (2-methyltetrazol-5-yl)-5-bromopyridine, 2 g of2-([1,2,3]triazol-1-yl)-5-bromopyridine as a starting material, toprepare the title compound 1.2 g.

¹H NMR (DMSO-d₆) δ 8.88 (s, 1H), 8.76 (s, 1H), 8.28 (d, 1H), 8.21 (d,1H), 8.01 (s, 1H), 7.70 (m, 2H), 7.51 (dd, 1H), 5.26 (t, 1H), 4.75 (m,1H), 4.14 (t, 1H), 3.90 (dd, 1H), 3.68 (m, 1H), 3.58 (m, 1H)

Example 6 Preparation of(R)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-on (compound 29)

The same procedure as in Example 1 was conducted, except for using,instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 1 g of2-([1,2,3]triazol-2-yl)-5-bromopyridine as a starting material, toprepare the title compound 0.7 g.

¹H NMR (DMSO-d₆) δ 8.74 (s, 1H), 8.25 (dd, 1H), 8.23 (s, 1H), 8.11 (d,1H), 7.69 (m, 3H), 7.49 (dd, 1H), 5.24 (t, 1H), 4.75 (m, 1H), 4.14 (t,1H), 3.89 (dd, 1H), 3.68 (m, 1H), 3.59 (m, 1H)

Example 7 Preparation of (R)-3-(4-(4-(4-cyanomethylthiazol-2-yl)phenyl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on(compound 32)

The same procedure as in Example 1 was conducted, except for using,instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 1 g of4-(4-cyanomethyl thiazol-2-yl)bromobenzene as a starting material, toprepare the title compound 520 mg.

¹H NMR (DMSO-d₆) δ 8.04 (s, 1H), 8.00 (s, 1H), 7.65 (m, 5H), 7.47 (dd,1H), 5.24 (t, 1H), 4.74 (m, 1H), 4.23 (s, 2H), 4.13 (t, 1H), 3.88 (dd,1H), 3.68 (m, 1H), 3.59 (m, 1H)

Example 8 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3,5-difluorophenyl)-5-hydroxymethyloxazolidin-2-on (compound 38)

The same procedure as in Example 1 was conducted, except for using,instead of(R)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol,(R)-3-(4-trimethylstannyl-3,4-difluorophenyl)-2-oxo-5-oxazolidinylmethanolas a starting material, to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.81 (s, 1H), 8.25 (d, 1H), 8.10 (d, 1H), 7.54 (d,2H), 5.25 (t, 1H), 4.77 (m, 1H), 4.47 (s, 3H), 4.13 (t, 1H), 3.89 (dd,1H), 3.68 (m, 1H), 3.57 (m, 1H)

Example 9 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3,4-difluorophenyl)-5-hydroxymethyloxazolidin-2-on (compound 39)

The same procedure as in Example 1 was conducted by using(R)-3-(4-trimethylstannyl-3,4-difluorophenyl)-2-oxo-5-oxazolidinylmethanol and2-(2-methyl-[1,3,4]oxadiazol-5-yl)-5-bromopyridine as a startingmaterial, to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.83 (s, 1H), 8.25 (d, 1H), 8.15 (d, 1H), 7.55 (d,2H), 5.25 (t, 1H), 4.77 (m, 1H), 4.13 (t, 1H), 3.89 (dd, 1H), 3.68 (m,1H), 3.59 (m, 1H), 2.63 (s, 3H)

Example 10 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyloxazolidin-2-on trifluoroacetic acid (compound 12)

In 25 ml of dimethylformamide was dissolved 4 g of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-on (compound 10). The solution was added 3.34 g of1,3-dicyclohexylcarbodiimide, 2.36 g of BOC-glycine and 0.2 g of4-dimethylaminopyridine at room temperature and then stirred for 10hours. The reaction mixture was added with water and extracted withethyl acetate. The organic layer, thus separated, was washed with brine,dehydrated, filtered, concentrated in vacuo and purified by columnchromatography. A residue, thus resulted in concentrating in vacuo, wasdissolved in 70 ml of methylenchloride, added with 30 ml oftrifluoroacetic acid, and stirred for 2 hours at room temperature. Theresidue was washed with ethanol and ethyl ether and concentrated invacuo to obtain the title compound 4.47 g. Yield 76%.

¹H NMR (DMSO-d₆) δ 8.92 (s, 1H), 8.19 (s, 3H), 8.17 (m, 2H), 7.77 (t,1H), 7.69 (dd, 1H), 7.49 (dd, 1H), 5.00 (m, 1H), 4.46 (m, 2H), 4.47 (s,3H), 4.24 (t, 1H), 3.92 (dd, 1H), 3.90 (s, 2H)

Example 11 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyloxazolidin-2-on trifluoroacetic acid (compound 20)

The title compound was prepared in a method similar to that of Example10 using BOC-valline, instead of BOC-glycine.

¹H NMR (DMSO-d₆) δ 8.92 (s, 1H), 8.40 (s, 3H), 8.21 (m, 2H), 7.76 (t,1H), 7.65 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.63 (dd, 1H), 4.47 (s,3H), 4.43 (dd, 1H), 4.28 (t, 1H), 4.01 (d, 1H), 3.93 (dd, 1H), 2.14 (m,1H), 0.98 (d, 3H), 0.95 (d, 3H)

Example 12 Preparation of (R)-3-(4-(2-[1,2,3]triazol-1-ylpyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl oxazolidin-2-ontrifluoroacetic acid (compound 22)

The title compound was prepared in a method similar to that of Example10 using compound 24.

¹H NMR (DMSO-d₆) δ 8.87 (s, 1H), 8.76 (s, 1H), 8.33 (s, 3H), 8.29 (d,1H), 8.00 (s, 1H), 7.77 (t, 1H), 7.76 (t, 1H), 7.67 (dd, 1H), 7.47 (dd,1H), 5.02 (m, 1H), 4.49 (m, 2H), 4.23 (t, 1H), 3.93 (m, 3H)

Example 13 Preparation of(R)-3-(4-(4-(4,5-dimethyloxazol-2-yl)phenyl)-3-fluorophenyl)-5-glycyloxymethyloxazolidin-2-on trifluoroacetic acid (compound 23)

The title compound was prepared in a method similar to that of Example10 using compound 21.

¹H NMR (DMSO-d₆) δ 8.31 (s, 3H), 7.97 (d, 2H), 7.64 (m, 4H), 7.45 (dd,1H), 5.01 (m, 1H), 4.47 (m, 2H), 4.25 (t, 1H), 3.94 (dd, 1H), 3.90 (s,2H)

Example 14 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyloxazolidin-2-on trifluoroacetic acid (compound 27)

The title compound was prepared in a method similar to that of Example10 using compound 16.

¹H NMR (DMSO-d₆) δ 8.96 (s, 1H), 8.31 (s, 3H), 8.22 (s, 2H), 7.76 (t,1H), 7.66 (dd, 1H), 7.50 (dd, 1H), 5.04 (m, 1H), 4.50 (m, 2H), 4.25 (t,1H), 3.94 (dd, 1H), 3.91 (s, 2H), 2.63 (s, 3H)

Example 15 Preparation of (R)-3-(4-(4-(4-cyanomethylthiazol-2-yl)phenyl)-3-fluorophenyl)-5-glycyloxymethyl oxazolidin-2-ontrifluoroacetic acid (compound 34)

The title compound was prepared in a method similar to that of Example10 using compound 32.

¹H NMR (DMSO-d₆) δ 8.25 (s, 3H), 8.03 (d, 2H), 7.68 (m, 5H), 7.44 (dd,1H), 5.01 (m, 1H), 4.48 (m, 2H), 4.25 (m, 3H), 3.92 (m, 3H)

Example 16 Preparation of(R)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyloxazolidin-2-on trifluoroacetic acid (compound 35)

The title compound was prepared in a method similar to that of Example10 using compound 29.

¹H NMR (DMSO-d₆) δ 8.78 (s, 1H), 8.23 (m, 2H), 8.22 (s, 3H), 8.20 (s,1H), 8.12 (d, 1H), 7.75 (t, 1H), 7.67 (dd, 1H), 7.48 (dd, 1H), 5.01 (m,1H), 4.49 (m, 2H), 4.24 (t, 1H), 3.92 (dd, 1H), 3.89 (s, 2H)

Example 17 Preparation of(S)-3-(4-(2-(2-oxo-4-glycyloxymethylpyrrolidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide trifluoroacetic acid (compound 1)

1. The Primary Step

In 14 ml of 1-methyl-2-pyrrolidon was dissolved 1.8 g of(S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide. The solution was added 1.03 g of2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine, 0.55 g oflithium chloride and 0.15 g of dichlorobistriphenylphosphine palladium(II) at room temperature and then stirred at the temperature of 110° C.for 2 hours. The reaction mixture was added with water and extractedwith ethyl acetate. After being washed with brine, the organic layer,thus separated, was dehydrated, filtered, concentrated in vacuo andpurified by column chromatography thereby to obtain(S)-3-(4-(2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide 410 mg. Yield 21%.

2. The Secondary Step

In dimethylformamide 2.3 ml was dissolved 50 mg of the compound preparedin the primary step. The solution was added with 35 mg of1,3-dicyclohexylcarbodiamide, 25 mg of BOC-glycine and 2.1 mg of4-dimethylaminopyridin at room temperature and then stirred for 10hours. The reaction mixture was added with water and extracted withethyl acetate. After being washed with brine, the organic layer, thusseparated, was dehydrated, filtrated, concentrated in vacuo and purifiedby column chromatography. A residue, provided by concentrating, wasdissolved in 2 ml of methylenchloride, added with 1 ml oftrifluoroacetic acid and then stirred for 2 hours at room temperature.The residue was washed with ethanol and ethyl ether, evaporated in vacuoto obtain the title compound 140 mg.

¹H NMR (DMSO-d₆) δ 8.60 (s, 1H), 8.40 (d, 1H), 8.28 (s, 3H), 8.25 (m,1H), 8.08 (dd, 1H), 7.63 (m, 2H), 7.42 (dd, 1H), 4.76 (m, 1H), 4.27 (s,2H), 4.16 (q, 2H), 3.87 (s, 2H), 3.80 (m, 2H), 3.42 (m, 2H), 2.62 (m,1H), 2.11 (m, 1H), 1.83 (s, 3H)

Example 18 Preparation of(S)-3-(4-(2-(4-glycyloxymethyl-[1,2,3]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide trifluoroacetic acid (compound 2)

The same procedure as in Example 17 was conducted, except for using,instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine,2-(4-hydroxymethyl-[1,2,3]triazol-1-yl)-5-bromopyridine as a startingmaterial, to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.96 (s, 1H), 8.89 (s, 1H), 8.22 (m, 6H), 7.74 (t,1H), 7.68 (dd, 1H), 7.48 (dd, 1H), 5.42 (s, 2H), 4.78 (m, 1H), 4.19 (t,1H), 3.91 (s, 2H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.83 (s, 3H)

Example 19 Preparation of(S)-3-(4-(2-(5-glycyloxymethylisoxazol-3-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide trifluoroacetic acid (compound 3)

The same procedure as in Example 17 was conducted, except for using,instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine,2-(5-hydroxymethylisoxazol)-5-bromopyridine as a starting material, toprepare the title compound.

¹H NMR (DMSO-d₆) δ 8.89 (s, 1H), 8.26 (s, 3H), 8.12 (m, 2H), 7.72 (t,1H), 7.64 (dd, 1H), 7.48 (dd, 1H), 7.21 (s, 1H), 5.49 (s, 2H), 4.77 (m,1H), 4.17 (t, 1H), 3.98 (s, 2H), 3.79 (m, 1H), 3.43 (m, 2H), 1.83 (s,3H)

Example 20 Preparation of(S)-3-(4-(2-(2-oxo-3-glycyloxypyrrolidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide trifluoroacetic acid (compound 5)

The same procedure as in Example 17 was conducted, except for using,instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine,2-(2-oxo-3-hydroxypyrrolidin-1-yl)-5-bromopyridine as a startingmaterial, to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.60 (s, 1H), 8.33 (d, 1H), 8.28 (s, 3H), 8.25 (m,1H), 8.05 (d, 1H), 7.63 (m, 2H), 7.42 (dd, 1H), 5.78 (t, 1H), 4.78 (m,1H), 4.16 (q, 2H), 3.98 (s, 2H), 3.85 (m, 1H), 3.78 (m, 1H), 3.43 (m,2H), 2.62 (m, 1H), 2.12 (m, 1H), 1.83 (s, 3H)

Example 21 Preparation of(S)-3-(4-(2-(5-glycyloxymethyl-[1,2,4]oxadiazol-3-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide trifluoroacetic acid (compound 6)

The same procedure as in Example 17 was conducted, except for using,instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine,2-(5-hydroxymethyl-[1,2,4]oxadiazol-3-yl)-5-bromopyridine as a startingmaterial, to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.95 (s, 1H), 8.32 (s, 3H), 8.21 (m, 3H), 7.75 (t,1H), 7.65 (dd, 1H), 7.47 (d, 1H) 5.67 (s, 1H), 4.78 (m, 1H), 4.18 (t,1H), 4.05 (s, 2H), 3.80 (m, 1H), 3.43 (m, 2H), 1.83 (s, 3H)

Example 22 Preparation of (S)-3-(4-(2-(5-glycyloxymethyl-4,5-dihydroisoxazol-3-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide trifluoro acetic acid (compound 7)

The same procedure as in Example 17 was conducted, except for using,instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine,2-(5-hydroxymethyl-4, 5-dihydroisoxazol-1-yl)-5-bromopyridine as astarting material, to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.81 (s, 1H), 8.27 (t, 1H), 8.24 (s, 3H), 8.05 (m,2H), 7.69 (m, 2H), 7.44 (d, 1H) 5.04 (m, 1H), 4.76 (m, 1H), 4.41 (dd,1H), 4.32 (m, 1H), 4.17 (t, 1H), 3.86 (s, 2H), 3.77 (m, 1H), 3.60 (m,1H), 3.44 (m, 2H), 1.83 (s, 3H)

Example 23 Preparation of(S)-3-(4-(4-(4-glycyloxymethylthiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide trifluoroacetic acid (compound 30)

The same procedure as in Example 17 was conducted, except for using,instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine,4-(4-hydroxymethyl thiazol-2-yl)-bromobenzene as a starting material, toprepare the title compound.

¹H NMR (DMSO-d₆) δ 8.25 (s, 3H), 8.00 (d, 2H), 7.85 (s, 1H), 7.69 (m,4H), 7.44 (dd, 1H), 5.63 (s, 2H), 4.76 (m, 1H), 4.16 (t, 1H), 3.93 (s,2H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.83 (s, 3H)

Example 24 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,4]triazol-1-yl)methyloxazolidin-2-on (compound 4) 1. The Primary Step

In 14 ml of methylenchloride was dissolved 1 g of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-on (compound 10). The solution was added with 0.46 g ofmethansulfonylchloride 0.46 g and 0.75 ml of triethylamine at roomtemperature and stirred at the same temperature for 30 minutes. Waterand brine were added to the reaction mixture for washing, followed byextraction. The organic layer was dehydrated, filtrated and concentratedin vacuo thereby to provide(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyloxazolidin-2-on 1 g. Yield 82%.

2. The Secondary Step

In 15 ml of dimethylformamide was dissolved the compound prepared in theprimary step. The solution was added with 300 mg of 1,2,4-triazol 300 mgand 100 mg of sodiumhydride (60%) at room temperature and stirred for 2days. The reaction mixture was extracted with ethyl acetate and then theorganic layer, thus separated, was washed with water and brine. Theorganic layer was dehydrated, filtered and concentrated in vacuo. Theresidue, prepared by concentrating, was purified by columnchromatography to provide the title compound 400 mg. Yield 43%.

¹H NMR (DMSO-d₆) δ 8.91 (s, 1H), 8.57 (s, 1H), 8.19 (m, 2H), 7.74 (t,1H), 7.58 (dd, 1H), 7.42 (dd, 1H), 5.13 (m, 1H), 4.64 (m, 2H), 4.46 (s,3H), 4.28 (t, 1H), 3.99 (dd, 1H)

Example 25 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-2-yl)methyloxazolidin-2-on (compound 8) and(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyloxazolidin-2-on (compound 9)

The same procedure as in Example 24 was conducted, except for adding,instead of 1,2,4-triazol, 1,2,3-triazol, to obtain compound 8 andcompound 9, and then the compounds were divided by columnchromatography.

(compound 8) ¹H NMR (DMSO-d₆) δ 8.90 (s, 1H), 8.19 (m, 2H), 7.82 (s,2H), 7.71 (t, 1H), 7.59 (dd, 1H) 7.41 (dd, 1H), 5.22 (m, 1H), 4.86 (m,2H), 4.46 (s, 3H), 4.30 (t, 1H), 3.98 (dd, 1H)

(compound 9) ¹H NMR (DMSO-d₆) δ 8.90 (s, 1H), 8.18 (m, 3H), 7.75 (s,1H), 7.72 (t, 1H), 7.59 (dd, 1H) 7.42 (dd, 1H), 5.22 (m, 1H), 4.86 (m,2H), 4.46 (s, 3H), 4.30 (t, 1H), 3.98 (dd, 1H)

Example 26 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyloxazolidin-2-on (compound 13)

The same procedure as in Example 24 was conducted, except for adding1,2,3-triazo and using the compound 16 as a starting material, to obtainthe title compound.

¹H NMR (DMSO-d₆) δ 8.92 (s, 1H), 8.20 (s, 2H), 8.17 (s, 1H), 7.75 (s,1H), 7.73 (t, 1H), 7.61 (dd, 1H) 7.43 (dd, 1H), 5.18 (m, 1H), 4.85 (m,2H), 4.29 (t, 1H), 3.96 (dd, 1H), 2.62 (s, 3H)

Example 27 Preparation of(R)-3-(4-(2-([1,2,4]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyloxazolidin-2-on (compound 14)

The same procedure as in Example 24 was conducted, except for adding1,2,3-triazol and using the compound 17 as a starting material, toobtain the title compound.

¹H NMR (DMSO-d₆) δ 9.40 (s, 1H), 8.70 (s, 1H), 8.32 (s, 2H), 8.25 (d,1H), 8.17 (s, 1H), 7.96 (d, 1H), 7.75 (s, 1H), 7.71 (t, 1H), 7.60 (dd,1H) 7.42 (dd, 1H), 5.18 (m, 1H), 4.86 (m, 2H), 4.29 (t, 1H), 3.96 (dd,1H)

Example 28 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoromethyloxazolidin-2-on (compound 18)

In 5 ml of methylenchloride was dissolved 100 mg of the compound 10. Thesolution was added with 43 mg of diethylaminosulfurtrifloride (DAST) and0.078 ml of triethylamine and then stirred for 24 hours. After beingconcentrating, the reaction mixture was purified by columnchromatography to obtain the title compound 75 mg. Yield 75%.

¹H NMR (DMSO-d₆) δ 8.91 (s, 1H), 8.19 (m, 2H), 7.74 (t, 1H), 7.66 (dd,1H) 7.49 (dd, 1H), 5.06 (m, 1H), 4.89 (m, 2H), 4.46 (s, 3H), 4.23 (t,1H), 3.95 (dd, 1H)

Example 29 Preparation of(S)-3-(4-(2-(imidazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-aminomethyloxazolidin-2-on hydrochloride (compound 19)

In 3.4 ml of ethanol and 30.6 ml of pyridin was dissolved 2.5 g of(S)-3-(4-(2-(imidazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide. The solution was added with 2.36 g of hydroxylamine at roomtemperature and stirred for 10 hours at the temperature 100° C. Thereaction mixture was extracted with ethyl acetate and the organic layer,thus separated, was washed with water and brine. The organic layer wasdehydrated, filtered and concentrated in vacuo. The residue, obtained byconcentrating, was purified by column chromatography and then dissolvedin tetrahydrofuran solution, saturated hydrochloric acid, and stirredfor 10 minutes. The solid, prepared by the above reaction, wasrecrystallized to provide the title compound 1g.

Example 30 Preparation of(S)-3-(4-(4-(4,5-dimethyloxazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide (compound 11)

The same procedure as in Example 1 was conducted, except for adding4-(4,5-dimethyloxazol-2-yl)-bromobenzene and using(S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide as a starting material, to obtain the title compound.

¹H NMR (DMSO-d₆) δ 8.24 (m, 1H), 7.96 (m, 2H), 7.62 (m, 4H), 7.45 (dd,1H), 4.78 (m, 1H), 4.16 (t, 1H), 3.79 (dd, 1H), 3.41 (m, 2H), 2.32 (s,3H), 2.10 (s, 3H), 1.83 (s, 3H)

Example 31 Preparation of(S)-3-(4-(2-(4,5-dimethyloxazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide (compound 15)

The same procedure as in Example 1 was conducted, except for adding4-(4,5-dimethyloxazol-2-yl)-5-bromopyridine and using(S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide as a starting material, to obtain the title compound.

¹H NMR (DMSO-d₆) δ 8.81 (s, 1H), 8.24 (t, 1H), 8.07 (m, 2H), 7.77 (t,1H), 7.62 (dd, 1H), 7.45 (dd, 1H), 4.78 (m, 1H), 4.18 (t, 1H), 3.79 (dd,1H), 3.42 (m, 2H), 2.35 (s, 3H), 2.12 (s, 3H), 1.84 (s, 3H)

Example 32 Preparation of(S)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide (compound 25)

The same procedure as in Example 1 was conducted, except for adding2-([1,2,3]triazol-2-yl)-5-bromopyridine and using(S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide as a starting material, to obtain the title compound.

¹H NMR (DMSO-d₆) δ 8.74 (s, 1H), 8.24 (m, 2H), 8.19 (s, 2H), 8.11 (d,1H), 7.72 (t, 1H), 7.64 (dd, 1H), 7.45 (dd, 1H), 4.79 (m, 1H), 4.18 (t,1H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.84 (s, 3H)

Example 33 Preparation of(S)-3-(4-(4-(4(S)-hydroxymethyl-4,5-dihydrooxazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide (compound 26)

The same procedure as in Example 1 was conducted, except for adding4-(4(S)-hydroxymethyl-4, 5-dihydro oxazol-2-yl)-bromobenzene and using(S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide as a starting material, to obtain the title compound.

¹H NMR (DMSO-d₆) δ 8.23 (t, 1H), 7.91 (d, 2H), 7.62 (m, 4H), 7.42 (dd,1H), 4.82 (t, 1H), 4.78 (m, 1H), 4.41 (t, 1H), 4.28 (m, 2H), 4.16 (t,1H), 3.79 (dd, 1H), 3.61 (m, 1H), 3.48 (m, 1H), 3.43 (m, 2H), 1.84 (s,3H)

Example 34 Preparation of (S)-3-(4-(4-(4-cyanomethylthiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide (compound 31)

The same procedure as in Example 1 was conducted, except for adding4-(4-cyanomethyl thiazol-2-yl)-bromobenzene and using(S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide as a starting material, to obtain the title compound.

¹H NMR (DMSO-d₆) δ 8.25 (t, 1H), 8.00 (d, 2H), 7.67 (m, 4H), 7.44 (dd,1H), 4.79 (m, 1H), 4.23 (s, 2H), 4.14 (t, 1H), 3.79 (dd, 1H), 3.43 (m,2H), 1.83 (s, 3H)

Example 35 Preparation of (R)-3-(4-(4-(4-hydroxymethylthiazol-2-yl)phenyl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyloxazolidin-2-on (compound 36)

The same procedure as in Example 1 was conducted, except for adding4-(4-hydroxymethyl thiazol-2-yl)-bromobenzene and using(R)-3-(4-trimethylstannyl-3-fluorophenyl)-5-[1,2,3]triazol-1-yloxazolidin-2-on as a starting material, to obtain the title compound.

¹H NMR (DMSO-d₆) δ 8.16 (s, 1H), 8.00 (d, 2H), 7.75 (s, 1H), 7.64 (dd,2H), 7.62 (t, 1H), 7.52 (dd, 1H), 7.48 (s, 1H), 7.36 (dd, 1H), 5.40 (t,1H), 5.18 (m, 1H), 4.85 (d, 2H), 4.62 (d, 2H), 4.28 (t, 1H), 3.95 (dd,1H)

Example 36 Preparation of (R)-3-(4-(4-(4-glycyloxymethylthiazol-2-yl)phenyl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyloxazolidin-2-on trifluoroacetic acid (compound 37)

The same procedure as in Example 10 was conducted, except for using(R)-3-(4-(4-(4-hydroxymethylthiazol-2-yl)phenyl)-3-fluorophenyl)-5-[1,2,3]triazol-1-ylmethyloxazolidin-2-on as a starting material, to obtain the title compound.

¹H NMR (DMSO-d₆) δ 8.29 (s, 3H), 8.17 (s, 1H), 8.00 (d, 2H), 7.85 (s,1H), 7.75 (s, 1H), 7.69 (dd, 2H), 7.67 (t, 1H), 7.55 (dd, 1H), 7.43 (dd,1H), 5.36 (s, 2H), 5.19 (m, 1H), 4.86 (d, 2H), 4.28 (t, 1H), 4.28 (t,1H)

Example 37 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methoxymethyloxazolidin-2-on (compound 33)

In 10 ml of methanol was dissolved 400 mg of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyloxazolidin-2-on prepared in the secondary step of the Example 24. Thesolution was added with 90 mg of sodiummethoxide at room temperature andthen stirred for one day at room temperature. The solution was extractedwith ethyl acetate and the organic layer, thus separated, was washedwith water and brine. The organic layer was dehydrated, filtered,concentrated in vacuo and purified by column chromatography to providethe title compound 200 mg. Yield 58%.

¹H NMR (CDCl₃) δ 8.90 (s, 1H), 8.29 (d, 1H), 8.04 (d, 1H), 7.61 (dd,1H), 7.58 (t, 1H), 7.38 (dd, 1H), 4.80 (m, 1H), 4.45 (s, 3H), 4.08 (t,1H), 3.96 (dd, 1H), 3.67 (m, 2H), 3.43 (s, 3H)

Example 38 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(N,N-dimethylaminomethyl)oxazolidin-2-on(compound 40)

In 5 ml of dimethylformamid was dissolved 100 mg of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyloxazolidin-2-on prepared in the secondary step of the Example 24. Thesolution was added with 30 mg of dimethylamine hydrochloride at roomtemperature. The solution was stirred for 30 hours at the temperature of60° C. And then the solution was extracted with ethyl acetate and theorganic layer, thus separated, was washed with water and brine. Theresidue, prepared by dehydrating, filtering and concentrating theorganic layer, was purified by column chromatography to provide thetitle compound 70 mg. Yield 76%.

¹H NMR (DMSO-d₆) δ 8.91 (s, 1H), 8.19 (m, 2H), 7.76 (t, 1H), 7.65 (dd,1H), 7.49 (dd, 1H), 4.98 (m, 1H), 4.63 (s, 3H), 4.27 (m, 3H), 3.94 (dd,1H), 2.79 (s, 3H), 2.74 (s, 3H)

Example 39 Preparation of(S)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-N-methylaminomethyloxazolidin-2-on (compound 41)

In 7 ml of dimethylformamid was dissolved 200 mg of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyloxazolidin-2-on, prepared in the primary step of the Example 24. Thesolution was added with 100 mg of methylamine hydrochloride and 240 mgof potasiumcarbonate at room temperature. The solution was stirred for30 hours at the temperature of 80° C. The solution was added with ethylacetate and then the organic layer, thus separated, was washed withwater and brine. The residue, prepared by dehydrating, filtering andconcentrating the organic layer, was purified by column chromatographyto obtain the title compound 80 mg. Yield 45%.

¹H NMR (DMSO-d₆) δ 8.91 (s, 1H), 8.18 (m, 2H), 7.73 (t, 1H), 7.66 (dd,1H), 7.47 (dd, 1H), 7.17 (m, 1H), 4.94 (m, 1H), 4.46 (s, 3H), 4.25 (m,3H), 3.85 (dd, 1H), 2.49 (d, 3H)

Example 40 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyl oxazolidin-2-on trifluoroacetic acid (compound 42)

The same procedure as in Example 10 was carried out to provide the titlecompound using BOC-L-alanine instead of BOC-glycine.

¹H NMR (DMSO-d₆) δ 8.91 (s, 1H), 8.42 (s, 3H), 8.20 (m, 2H), 7.75 (t,1H), 7.67 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.61 (dd, 1H), 4.46 (s,3H), 4.41 (dd, 1H), 4.26 (t, 1H), 4.18 (m, 1H), 3.96 (dd, 1H), 1.36 (d,3H)

Example 41 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyl oxazolidin-2-on hydrochloride (compound 43)

500 mg of compound 20, prepared in Example 11, was dissolved in water.The solution was controlled to pH 5 with the addition of sodiumbicarbonate aqueous solution. The aqueous layer was extracted with ethylacetate and then the organic layer was slowly added with ether solutionsaturating of hydrochloric acid. The solid prepared by the above methodwas filtered and concentrated in vacuo to provide the title compound 200mg. Yield 46%.

¹H NMR (DMSO-d₆) δ 8.92 (s, 1H), 8.54 (bs, 3H), 8.20 (m, 2H), 7.76 (t,1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.58 (dd, 1H), 4.46 (s,3H), 4.41 (dd, 1H), 4.26 (t, 1H), 3.95 (m, 2H), 2.17 (m, 1H), 0.97 (d,3H), 0.94 (d, 3H)

Example 42 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyloxazolidin-2-on hydrochloride (compound 44)

With the exception of using compound 42, the same procedure as inExample 41 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.92 (s, 1H), 8.52 (bs, 3H), 8.20 (m, 2H), 7.75 (t,1H), 7.66 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.60 (dd, 1H), 4.46 (s,3H), 4.41 (dd, 1H), 4.26 (t, 1H), 4.18 (m, 1H), 4.00 (dd, 1H), 1.37 (d,3H)

Example 43 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyloxazolidin-2-on hydrochloride (compound 45)

With the exception of using the compound 12, the same procedure as inExample 41 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.91 (s, 1H), 8.48 (bs, 3H), 8.18 (m, 2H), 7.75 (t,1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.03 (m, 1H), 4.48 (m, 2H), 4.46 (s,3H), 4.24 (t, 1H), 3.99 (dd, 1H), 3.86 (m, 2H)

Example 44 Preparation of(S)-3-(4-(4-(4-hydroxymethylthiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide (compound 28)

With the exception of using(S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethylacetamide as a starting material and4-(4-hydroxymethylthiazol-2-yl)-bromobenzene, the same procedure as inExample 1 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.24 (t, 1H), 7.98 (d, 2H), 7.65 (m, 2H), 7.59 (m,2H), 7.43 (s, 1H), 7.41 (dd, 1H), 5.40 (t, 1H), 4.79 (m, 1H), 4.63 (d,2H), 4.16 (t, 1H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.84 (s, 3H)

Example 45(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-prolinyloxy)methyloxazolidin-2-on trifluoroacetic acid (compound 46)

With the exception of using BOC-L-proline, instead of BOC-glycine, thesame procedure as in Example 10 was conducted to prepare the titlecompound.

¹H NMR (DMSO-d₆) δ 9.25 (bs, 2H), 8.91 (s, 1H), 8.20 (m, 2H), 7.76 (t,1H), 7.65 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.57 (dd, 1H), 4.45 (s,3H), 4.41 (dd, 1H), 4.26 (t, 1H), 3.96 (dd, 1H), 3.23 (m, 2H), 2.21 (m,1H), 1.92 (m, 3H)

Example 46 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-prolinyloxy)methyloxazolidin-2-on hydrochloride (compound 47)

With the exception of using the compound 46, the same procedure as inExample 41 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 9.11 (bs, 2H), 8.91 (s, 1H), 8.20 (m, 2H), 7.76 (t,1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.55 (dd, 1H), 4.46 (s,3H), 4.41 (dd, 1H), 4.25 (t, 1H), 4.01 (dd, 1H), 3.36 (m, 2H), 2.07 (m,1H), 1.89 (m, 3H)

Example 47 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyloxazolidin-2-on hydrochloride (compound 48)

With the exception of using the compound 27, the same procedure as inExample 41 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.92 (s, 1H), 8.48 (s, 3H), 8.21 (s, 2H), 7.76 (t,1H), 7.66 (dd, 1H), 7.48 (dd, 1H), 5.04 (m, 1H), 4.47 (m, 2H), 4.23 (t,1H), 3.94 (m, 1H), 3.84 (d, 2H), 2.62 (s, 3H)

Example 48 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyloxazolidin-2-on trifluoroacetic acid (compound 49)

With the exception of using BOC-β-alanine, instead of BOC-glycine, thesame procedure as in Example 10 was conducted to prepare the titlecompound.

¹H NMR (DMSO-d₆) δ 8.91 (s, 1H), 8.20 (m, 2H), 7.75 (t, 1H), 7.73 (bs,3H), 7.68 (dd, 1H), 7.48 (dd, 1H), 5.02 (m, 1H), 4.46 (s, 3H), 4.36 (m,2H), 4.26 (t, 1H), 3.93 (dd, 1H), 3.02 (m, 2H), 2.70 (t, 2H)

Example 49 Preparation of(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyloxazolidin-2-on hydrochloride (compound 50)

With the exception of using the compound 49, the same procedure as inExample 41 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.91 (s, 1H), 8.22 (m, 2H), 8.11 (bs, 3H), 7.76 (t,1H), 7.65 (dd, 1H), 7.48 (dd, 1H), 5.02 (m, 1H), 4.46 (s, 3H), 4.36 (m,2H), 4.23 (t, 1H), 3.95 (m, 1H), 3.00 (m, 2H), 2.74 (t, 2H)

Example 50 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyloxazolidin-2-on trifluoroacetic acid (compound 51)

With the exception of using the compound 16 and BOC-L-alanine, the sameprocedure as in Example 10 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.93 (s, 1H), 8.39 (bs, 3H), 8.21 (s, 2H), 7.76 (t,1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.61 (dd, 1H), 4.40(dd, 1H), 4.28 (t, 1H), 4.18 (dd, 1H), 3.95 (dd, 1H), 2.62 (s, 3H), 1.36(d, 3H)

Example 51 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyloxazolidin-2-on hydrochloride (compound 52)

With the exception of using the compound 51, the same procedure as inExample 41 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.93 (s, 1H), 8.61 (bs, 3H), 8.21 (s, 2H), 7.76 (t,1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.58 (dd, 1H), 4.39(dd, 1H), 4.25 (t, 1H), 4.12 (m, 1H), 4.00 (dd, 1H), 2.62 (s, 3H), 1.36(d, 3H)

Example 52 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyloxazolidin-2-on trifluoroacetic acid (compound 53)

With the exception of using the compound 16 and BOC-L-valline, the sameprocedure as in Example 10 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.93 (s, 1H), 8.40 (bs, 3H), 8.21 (s, 2H), 7.75 (t,1H), 7.68 (dd, 1H), 7.48 (dd, 1H), 5.04 (m, 1H), 4.62 (dd, 1H), 4.40(dd, 1H), 4.26 (t, 1H), 3.99 (d, 1H), 3.92 (dd, 1H), 2.62 (s, 3H), 2.12(m, 1H), 0.97 (d, 3H), 0.94 (d, 3H)

Example 53 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyloxazolidin-2-on hydrochloride (compound 54)

With the exception of using the compound 53, the same procedure as inExample 41 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.93 (s, 1H), 8.60 (bs, 3H), 8.21 (s, 2H), 7.75 (t,1H), 7.67 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.58 (dd, 1H), 4.42(dd, 1H), 4.26 (t, 1H), 3.92 (m, 1H), 2.62 (s, 3H), 2.12 (m, 1H), 0.97(d, 3H), 0.94 (d, 3H)

Example 54 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-prolinyloxy)methyloxazolidin-2-on trifluoroacetic acid (compound 55)

With the exception of using the compound 16 and BOC-L-pyrroline, thesame procedure as in Example 10 was conducted to prepare the titlecompound.

¹H NMR (DMSO-d₆) δ 9.20 (bs, 2H), 8.93 (s, 1H), 8.21 (s, 2H), 7.77 (t,1H), 7.66 (dd, 1H), 7.50 (dd, 1H), 5.04 (m, 1H), 4.59 (dd, 1H), 4.43 (m,2H), 4.26 (t, 1H), 3.96 (dd, 1H), 3.21 (m, 2H), 2.62 (s, 3H), 2.21 (m,1H), 1.95 (m, 1H), 1.89 (m, 2H)

Example 55 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-prolinyloxy)methyloxazolidin-2-on hydrochloride (compound 56)

With the exception of using the compound 55, the same procedure as inExample 41 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 9.18 (bs, 2H), 8.93 (s, 1H), 8.21 (s, 2H), 7.76 (t,1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.57 (dd, 1H), 4.43 (m,2H), 4.26 (t, 1H), 4.00 (dd, 1H), 3.21 (m, 2H), 2.62 (s, 3H), 2.21 (m,1H), 1.95 (m, 1H), 1.89 (m, 2H)

Example 56 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyloxazolidin-2-on trifluoroacetic acid (compound 57)

With the exception of using the compound 16 and BOC-β-alanine, the sameprocedure as in Example 10 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.92 (s, 1H), 8.21 (s, 2H), 7.88 (bs, 3H), 7.76 (t,1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 5.02 (m, 1H), 4.36 (m, 2H), 4.25 (t,1H), 3.94 (dd, 1H), 3.03 (m, 2H), 2.70 (t, 2H), 2.62 (s, 3H)

Example 57 Preparation of(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyloxazolidin-2-on hydrochloride (compound 58)

With the exception of using the compound 57, the same procedure as inExample 41 was conducted to prepare the title compound.

¹H NMR (DMSO-d₆) δ 8.92 (s, 1H), 8.21 (s, 2H), 8.08 (bs, 3H), 7.76 (t,1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 5.02 (m, 1H), 4.36 (m, 2H), 4.25 (t,1H), 3.96 (dd, 1H), 3.00 (m, 2H), 2.71 (t, 2H), 2.62 (s, 3H)

Example 58 Preparation ofmono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate(compound 72) and(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyldisodiumphosphate (compound 59)

1. The Primary Step

In 10 ml of mixture solvent (tetrahydrofuran:methylenchloride=1:1) wasdissolved 1 g of compound 10. The solution was added with 0.6 g oftetrazole and 2.3 g of di-tetrabuthyl diisoprophylphosphoamidite andstirred for 15 hours at room temperature. The reaction mixture wasrefrigerated to −78° C., added with 0.7 g of metachloroperbenzoic acidand stirred for 2 hours. After being cooling to −78° C., the reactionmixture was added with metachloroperbenzoic acid (0.7 g). When thereaction mixture was stirred for 2 hours, the temperature of thereaction mixture was raised to room temperature. The reaction mixturewas then added with ethyl acetate. The organic layer, thus separated,was washed with sodiumbisulfate, sodiumbicarbonate and brine,dehydrated, filtered and concentrated in vacuo, followed by purificationwith column chromatography thereby to provide(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methylphosphoric acid ditetrabuthylester (0.71 g, 71%).

¹H NMR (DMSO-d₆) δ 8.90 (s, 1H), 8.18 (m, 2H), 7.74 (t, 1H), 7.68 (dd,1H), 7.49 (dd, 1H), 4.98 (m, 1H), 4.46 (s, 3H), 4.23 (t, 1H), 4.18 (m,1H), 4.09 (m, 1H), 3.89 (dd, 1H), 1.39 (s, 9H), 1.38 (s, 9H)

The crystal prepared the above method was dissolved in a mixture ofmethanol and chloroform. And then the solution added with 3.4 ml ofsodiummethoxide (0.3M methanol solution) at the room temperature andstirred for 10 hours. The reaction mixture was concentrated to preparethe residue. The residue was crystallized and filtered thereby to obtainthe title compound (compound 59) 300 mg.

¹H NMR (D₂O) δ 8.27 (s, 1H), 7.56 (dd, 2H), 7.06 (m, 2H), 6.90 (m, 1H),4.79 (m, 1H), 4.63 (s, 3H), 3.90 (m, 4H)

2. The Secondary Step

In 30 ml of methylenchloride was dissolved the compound (0.7 g) in thePrimary Step. The solution was added with 15 ml of trifluoroacetic acidand then stirred for 1 hour at room temperature. The reaction mixturewas concentrated in vacuo to prepare the residue. The residue wascrystallized with ethanol and ethyl ether to obtainmono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate(compound 72) 400 mg.

¹H NMR (DMSO-d₆) δ 8.92 (s, 1H), 8.20 (m, 2H), 7.74 (t, 1H), 7.66 (dd,1H), 7.500 (dd, 1H), 4.95 (m, 1H), 4.46 (s, 3H), 4.21 (t, 1H), 4.05 (m,2H), 3.91 (dd, 1H)

Example 59 Preparation of(R)-[3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyldisodiumphosphate (compound 60)

Using the compound 16, the title compound was prepared in a mannersimilar to that of the Example 58.

¹H NMR (D₂O) δ 8.33 (s, 1H), 7.65 (dd, 2H), 7.17 (m, 2H), 6.90 (m, 1H),4.79 (m, 1H), 4.63 (s, 3H), 3.94 (t, 1H), 3.78 (m, 3H)

Example 60 Preparation of(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-on (compound 61)

Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound wasprepared in a manner similar to that of the Example 1.

¹H NMR (DMSO-d₆) δ 8.98 (s, 1H), 8.30 (m, 2H), 7.75 (m, 2H), 7.53 (dd,1H), 5.25 (t, 1H), 4.76 (m, 1H), 4.44 (s, 3H), 4.14 (t, 1H), 3.89 (dd,1H), 3.69 (m, 1H), 3.58 (m, 1H)

Example 61 Preparation of(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyloxazolidin-2-on trifluoroacetic acid (compound 62)

Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound wasprepared in a manner similar to that of the Example 10.

¹H NMR (DMSO-d₆) δ 8.95 (s, 1H), 8.20 (s, 3H), 8.19 (m, 2H), 7.80 (t,1H), 7.69 (dd, 1H), 7.49 (dd, 1H), 5.00 (m, 1H), 4.46 (m, 2H), 4.45 (s,3H), 4.24 (t, 1H), 3.92 (dd, 1H), 3.90 (s, 2H)

Example 62 Preparation of(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyloxazolidin-2-on hydrochloride (compound 63)

Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound wasprepared in a manner similar to that of the Example 43.

¹H NMR (DMSO-d₆) δ 8.95 (s, 1H), 8.50 (bs, 3H), 8.21 (m, 2H), 7.80 (t,1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.03 (m, 1H), 4.48 (m, 2H), 4.43 (s,3H), 4.24 (t, 1H), 3.99 (dd, 1H), 3.86 (m, 2H)

Example 63 Preparation of(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyloxazolidin-2-on trifluoroacetic acid (compound 64)

Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound wasprepared in a manner similar to that of the Example 40.

¹H NMR (DMSO-d₆) δ 8.95 (s, 1H), 8.43 (s, 3H), 8.25 (m, 2H), 7.77 (t,1H), 7.68 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.63 (dd, 1H), 4.44 (s,3H), 4.42 (dd, 1H), 4.24 (t, 1H), 4.18 (m, 1H), 3.98 (dd, 1H), 1.36 (d,3H)

Example 64 Preparation of(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyloxazolidin-2-on hydrochloride (compound 65)

Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound wasprepared in a manner similar to that of the Example 42.

¹H NMR (DMSO-d₆) δ 8.95 (s, 1H), 8.53 (bs, 3H), 8.24 (m, 2H), 7.77 (t,1H), 7.67 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.60 (dd, 1H), 4.43 (s,3H), 4.42 (dd, 1H), 4.26 (t, 1H), 4.20 (m, 1H), 4.00 (dd, 1H), 1.37 (d,3H)

Example 65 Preparation of(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyloxazolidin-2-on trifluoroacetic acid (compound 66)

Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound wasprepared in a manner similar to that of the Example 11.

¹H NMR (DMSO-d₆) δ 8.95 (s, 1H), 8.42 (s, 3H), 8.25 (m, 2H), 7.79 (t,1H), 7.70 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.64 (dd, 1H), 4.44 (s,3H), 4.43 (dd, 1H), 4.30 (t, 1H), 4.01 (d, 1H), 3.93 (dd, 1H), 2.14 (m,1H), 0.98 (d, 3H), 0.95 (d, 3H)

Example 66 Preparation of(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyloxazolidin-2-on hydrochloride (compound 67)

Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound wasprepared in a manner similar to that of the Example 41.

¹H NMR (DMSO-d₆) δ 8.94 (s, 1H), 8.57 (bs, 3H), 8.22 (m, 2H), 7.79 (t,1H), 7.67 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.59 (dd, 1H), 4.43 (s,3H), 4.41 (dd, 1H), 4.27 (t, 1H), 3.99 (m, 2H), 2.17 (m, 1H), 0.97 (d,3H), 0.94 (d, 3H)

Example 67 Preparation of(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyloxazolidin-2-on trifluoroacetic acid (compound 68)

Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound wasprepared in a manner similar to that of the Example 48.

¹H NMR (DMSO-d₆) δ 8.94 (s, 1H), 8.24 (m, 2H), 7.77 (t, 1H), 7.73 (bs,3H), 7.70 (dd, 1H), 7.49 (dd, 1H), 5.02 (m, 1H), 4.44 (s, 3H), 4.36 (m,2H), 4.27 (t, 1H), 3.93 (dd, 1H), 3.05 (m, 2H), 2.70 (t, 2H)

Example 68 Preparation of(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyloxazolidin-2-on hydrochloride (compound 69)

Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound wasprepared in a manner similar to that of the Example 49.

¹H NMR (DMSO-d₆) δ 8.96 (s, 1H), 8.25 (m, 2H), 8.13 (bs, 3H), 7.79 (t,1H), 7.66 (dd, 1H), 7.48 (dd, 1H), 5.02 (m, 1H), 4.43 (s, 3H), 4.36 (m,2H), 4.25 (t, 1H), 3.97 (m, 1H), 3.01 (m, 2H), 2.74 (t, 2H)

Example 69 Preparation ofmono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate(compound 73) and(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyldisodiumphosphate (compound 70)

1. The Primary Step

Using the compound 61,(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methylphosphoric acid ditetrabuthylester was prepared in a manner similar tothat of the Example 58.

¹H NMR (DMSO-d₆) δ 8.94 (s, 1H), 8.20 (m, 2H), 7.78 (t, 1H), 7.68 (dd,1H), 7.49 (dd, 1H), 4.98 (m, 1H), 4.44 (s, 3H), 4.21 (t, 1H), 4.18 (m,1H), 4.10 (m, 1H), 3.89 (dd, 1H), 1.39 (s, 9H), 1.38 (s, 9H)

2. The Secondary Step

Using the compound provided in the Primary Step, 400 mg ofmono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate(compound 73) was prepared in a manner similar to that of the Example 58

¹H NMR (DMSO-d₆) δ 8.95 (s, 1H), 8.23 (m, 2H), 7.76 (t, 1H), 7.66 (dd,1H), 7.500 (dd, 1H), 4.95 (m, 1H), 4.44 (s, 3H), 4.21 (t, 1H), 4.05 (m,2H), 3.91 (dd, 1H)

The title compound (compound 70) was obtained in a manner similar tothat of the Example 58.

¹H NMR (D₂O) δ 8.29 (s, 1H), 7.60 (dd, 2H), 7.10 (m, 2H), 6.90 (m, 1H),4.79 (m, 1H), 4.60 (s, 3H), 3.90 (m, 4H)

Example 70 Preparation of(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyloxazolidin-2-on (compound 71)

Using the compound 61, the title compound was prepared in a mannersimilar to that of the Example 24.

¹H NMR (DMSO-d₆) δ 8.95 (s, 1H), 8.21 (m, 3H), 7.77 (s, 1H), 7.75 (t,1H), 7.59 (dd, 1H) 7.42 (dd, 1H), 5.22 (m, 1H), 4.86 (m, 2H), 4.44 (s,3H), 4.31 (t, 1H), 3.98 (dd, 1H)

Experimental Example 1 Assay for In Vitro Antibacterial Activity

To test an antibacterial activity of the derivatives of oxazolidinone,the antibacterial activity, including methicillin resistantStaphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE),was represented as Minimum Inhibitory Concentration (MIC₅₀, μg/ml) usingagar dilution described in a art (Chemotherapy, 29(1), 76, (1981)).Zyvox of Pharmacia & Upjohn Inc, corresponding to Formula 3, was used ascontrol. The results are shown in Table 2.

TABLE 2 Minimum Inhibitory Concentration (MIC₅₀, μg/ml) Compound MRSAVRE Zyvox 2 2 1 1 0.25 2 0.5 0.125 3 0.25 0.25 4 2 2 5 0.5 0.25 6 NA NA7 0.5 0.5 8 16 16 9 0.25 0.125 10 0.5 0.25 11 0.5 0.25 12 0.5 0.25 130.25 0.25 14 0.25 0.25 15 1 1 16 0.5 1 17 1 1 18 1 2 19 32 32 20 0.50.25 21 1 1 22 1 1 23 2 2 24 0.5 0.5 25 0.25 0.125 26 0.5 0.5 27 0.5 128 0.5 0.5 29 0.5 1 30 0.5 0.5 31 0.5 0.5 32 0.5 1 33 2 2 34 1 1 35 1 136 0.5 0.5 37 0.5 0.5 38 0.5 1 39 1 1 40 4 8 41 4 8 42 0.5 0.25 43 0.50.25 44 0.5 0.25 45 0.5 0.25 46 0.5 0.25 47 0.5 0.25 48 0.5 1 49 0.50.25 50 0.5 0.25 51 0.5 1 52 0.5 1 53 0.5 1 54 0.5 1 55 0.5 1 56 0.5 157 0.5 1 58 0.5 1 59 0.5 0.25 60 0.5 1 61 0.5 0.25 62 0.5 0.25 63 0.50.25 64 0.5 0.25 65 0.5 0.25 66 0.5 0.25 67 0.5 0.25 68 0.5 0.25 69 0.50.25 70 0.5 0.25 71 0.5 0.125 72 32 32 73 32 32 NA: Not determined MRSA:methicillin resistant Staphylococcus aureus VRE: vancomycin resistantEnterococci

As illustrated in Table 2, the derivatives of the present invention hadsufficient efficiency on antibacterial activity against Staphylococcusaureus (MRSA) and Enterococci (VRE) in spite of using lowerconcentration of the derivatives than that of the Zyvox. Accordingly,the compounds of the present invention may be useful as antibiotics.

(i) Experimental Example 2 Assay for Solubility

To test a solubility of the derivatives of the present invention, anexperiment was carried out below. The derivatives of the presentinvention were added to 200 μl of distilled water and then the solutionwas stirred for 2 minutes. The turbidity of the solution was watchedthrough naked eye.

When the derivatives were not dissolved completely, 50 μl of distilledwater was added to the solution and then the turbidity of the solutionwas assayed in the above manner to find a point of becoming transparentsolution.

When 2 mg of the derivatives was first added to distilled water andcompletely dissolved so that the solution became transparent, 2 mg ofthe derivatives was added more to the solution and then state of thesolution was watched. The derivatives of the present invention wereadded to the five times and then solubility of the solution was assayedfor. The assay for solubility was carried out the three times repeatedlyin the above method and the results were averaged. The averages wereshown in Table 3.

TABLE 3 Compound Solubility Zyvox 3 mg/ml 10 10 μg/ml 12 28 mg/ml 16 20μg/ml 20 4.7 mg/ml 27 >50 mg/ml 42 >50 mg/ml 43 4.2 mg/ml 44 >50 mg/ml45 12 mg/ml 46 <1.63 mg/ml 47 2 mg/ml 48 >50 mg/ml 49 2.6 mg/ml 50 20.4mg/ml 51 >50 mg/ml 52 >50 mg/ml 53 30.3 mg/ml 54 2.9 mg/ml 55 7.2 mg/ml56 >50 mg/ml 57 >50 mg/ml 58 5.5 mg/ml 59 >50 mg/ml 60 >50 mg/ml 62 28mg/ml 64 >50 mg/ml 66 4.7 mg/ml 68 2.6 mg/ml 70 >50 mg/ml

As shown in table 3, the solubility of the compound 42 (>50 mg/ml) thatis prodruged, of the derivatives was enhanced as compared with those ofZyvox (3 mg/ml) and the compound 10 (10 μg/ml).

Accordingly, when the derivatives of the present invention wereformulated for oral administration, absorption of the derivatives may beenhanced. When the derivatives were formulated as injection, variousformations of the derivatives may be obtained.

Experimental Example 3 Test of Acute Toxicity by Oral Administrating theDerivatives to Mouse

To test acute toxicity of the compounds of the present invention, thefollowing experiment was carried out.

A mixture of 1% hydroxyprophylmethylcellulose and 200 mg of one selectedfrom the group consisting of the compounds 10, 12, 16, 17, 20, 22, 24and 27 was administrated to 5 ICR mice (5-Week old males, 20 g±2 g byweight). And then lethality for 2 weeks, weight, symptoms etc. waswatched to determine Minimum Lethal Dose (MLD, mg/kg). Zyvox ofPharmacia & Upjohn Inc was used as control. The results were representedin Table 4.

TABLE 4 Compound Minimum Lethal Dose (MLD, mg/kg) Zyvox >1000 10 >100012 >1000 16 >1000 17 >1000 20 >1000 22 >1000 24 >1000 27 >1000

Observation of survival, change in weight, tests in blood, and toxicitysyndrome, etc. proved that administration of the composition of thepresent invention has no toxic effects

The compounds of the present invention have excellent efficiency onantibacterial activity without any toxicity present according to Table4.

Example Formulation Preparation of Pharmaceutical Composition

Preparation as Powder

Derivative of oxazolidinone 2 g Lactose 1 g

The above materials were mixed and then the mixture was filled into aclosed pack to prepare as powder.

Preparation as Tablet

Derivative of oxazolidinone 500 mg Corn starch 100 mg Lactose 100 mgMagneisuim stearate 2 mg

The above materials were mixed and then the mixture was tabletted by theknown method to prepare as tablet.

3. Preparation of Capsule

Derivative of oxazolidinone 500 mg Corn starch 100 mg Lactose 100 mgMagneisuim stearate 2 mg

The above materials were mixed and the mixture was filled into gelatincapsule by the known method to prepare as capsule.

4. Preparation of Injection

Derivative of oxazolidinone 500 mg Citrate buffer maintaining of pH 3.5Dextrose isotonicity

The derivative of oxazolidine, salt of sodium citrate, citratic acid anddextrose were filled in 20 ml of vial, sterilized, for injection andthen sealed off using aluminum cap. The mixture was dissolved indistilled water for injection and then diluted in distilled watersolution, having appropriate volume, for injection.

1-21. (canceled)
 22. A method of treating a bacterial infection in asubject, comprising administering to the subject an amount of thecompound of the following formula:

wherein R7 is hydrogen or PO(OH)₂.
 23. The method of claim 22, whereinthe bacterial infection results from a Gram-positive bacterium.
 24. Themethod of claim 22, wherein the bacterial infection results from abacterium that is selected from the group consisting of Staphylococcus,Enterococcus, Streptococcus, Bacteroides, Clostridium, andMycobacterium.
 25. The method of claim 23, wherein the Gram-positivebacterium is selected from the group consisting of Staphylococcus,Enterococcus, and Streptococcus.
 26. The method of claim 25 wherein, inthe compound, R7 is PO(OH)₂.
 27. The method of claim 25 wherein, in thecompound, R7 is hydrogen.
 28. The method of claim 22, wherein thecompound has the following structure:


29. The method of claim 22, wherein in the compound, R7 is hydrogen. 30.A method of treating a bacterial infection in a subject, comprisingadministering to the subject an amount of a pharmaceutically acceptablesalt of a compound, the compound having the following formula:

wherein R7 is hydrogen or PO(OH)₂.
 31. The method of claim 30, whereinthe bacterial infection results from a Gram-positive bacterium.
 32. Themethod of claim 30, wherein the bacterial infection results from abacterium that is selected from the group consisting of Staphylococcus,Enterococcus, Streptococcus, Bacteroides, Clostridium, andMycobacterium.
 33. The method of claim 31, wherein the Gram-positivebacterium is selected from the group consisting of Staphylococcus,Enterococcus, and Streptococcus.
 34. The method of claim 33 wherein, inthe compound, R7 is PO(OH)₂.
 35. The method of claim 33 wherein, in thecompound, R7 is hydrogen.
 36. The method of claim 30, wherein thecompound has the following structure:


37. The method of claim 36, wherein the pharmaceutically acceptable saltis a disodium salt.
 38. The method of claim 30, wherein in the compound,R7 is hydrogen.
 39. The method of claim 38, wherein the pharmaceuticallyacceptable salt is a disodium salt.